Excitatory amino acids such as L-glutamic acid and L-aspartic acid are known to be central nervous system neurotransmitters. It is believed that excessive excitation by the excitatory amino acids causes neurodegeneration observed in Huntington's chorea, Parkinson's disease, epilepsy, Alzheimer's disease, senile dementia, cerebral ischemia, anoxia, diabetes, hypoglycemia, drug dependence, head injury, etc, which leads to deficiency in mental and motor functions. Therefore, an agent which can control abnormality of the excitatory amino acid function is considered to be useful for protection from the aforementioned neurodegenerative diseases and psychiatric diseases. Further, recent studies show that such an agent is useful also for amyotrophic lateral sclerosis, multiple sclerosis, pain, glaucoma, etc.
Excitatory amino acids exert the effect via specific receptors located in postsynaptic or presynaptic sites. At present, based on electrophysiologic and neurobiochemical evidences, the receptors are classified into the following three groups:
1) NMDA (N-methyl-D-aspartate) receptor; PA1 2) Non-NMDA receptor; PA1 3) Metabotropic glutamate receptor PA1 R.sup.2 : a group represented by the formula ##STR5## or a mono- or oligocycloalkane which may have a lower alkyl group as a substituent and may have nitrogen atom(s); PA1 B: a bond or a lower alkylene group; PA1 the ring D: a 5- or 6-membered aromatic ring which may have one or two of one or more types of hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom; PA1 R.sup.6 and R.sup.7 : may be the same or different and each represent a hydrogen atom, a lower alkyl group which may have substituent(s), a lower alkanoyl group, a cycloalkyl group, an aryl group, a hydroxyl group, a lower alkoxy group, a halogeno-lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a halogen atom, a nitro group, a cyano group, an amino group, a mono- or di-lower alkylamino group, a hydroxylamino group or a lower alkoxyamino group, with the proviso that R.sup.6 and R.sup.7 may together form a 5- to 7-membered ring which may have one or two of one or more types of hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom and may have a lower alkyl group as a substituent); PA1 with the proviso that R.sup.2 and R.sup.3 may together form a 5- to 7-membered nitrogen-containing heterocyclic group which may have a nitrogen atom as another hetero atom, may be fused with a benzene ring which may have substituent(s) and may have substituent(s); and PA1 R.sup.4 and R.sup.5 : may be the same or different and each represent a hydrogen atom, a lower alkyl group, a carboxyl group, a lower alkoxycarbonyl group or an aryl group. PA1 R.sup.2 : a group represented by the formula ##STR8## or a mono- or oligocycloalkane which may have a lower alkyl group as a substituent and may have nitrogen atom(s); PA1 B: a bond or lower alkylene group; PA1 R.sup.6 and R.sup.7 : may be the same or different and each represent a hydrogen atom, a lower alkyl group which may have substituent(s), a lower alkanoyl group, a cycloalkyl group, an aryl group, a hydroxyl group, a lower alkoxy group, a halogeno-lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a halogen atom, a nitro group, a cyano group, an amino group, a mono- or di-lower alkylamino group, a hydroxylamino group or a lower alkoxyamino group, with the proviso that R.sup.6 and R.sup.7 may together form a 5- to 7-membered ring which may have one or two of one or more types of hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom and may have a lower alkyl group as a substituent); PA1 with the proviso that R.sup.2 and R.sup.3 may together form (1) a 5- to 7-membered nitrogen-containing heterocyclic group which may have substituent(s) and which may have a nitrogen atom as another hetero atom, or PA1 (2) a 5- to 7-membered nitrogen-containing heterocyclic group which may be fused with a benzene ring which may have substituent(s), which may have a nitrogen atom as another hetero atom, and which may have substituent(s); and PA1 R.sup.4 and R.sup.5 may be the same or different and each represent a hydrogen atom, a lower alkyl group, a carboxyl group, a lower alkoxycarbonyl group or an aryl group; PA1 with the proviso that when one of R.sup.1 and R.sup.3 is a methyl group and B is a bond, one of R.sup.6 and R.sup.7 represents a group other than a hydrogen atom.
a) AMPA (2-amino-3-(3-hydroxy-5-methyl-4-isoxazole)propionate)/kainate receptor, PA2 b) kainate receptor; and
L-glutamic acid or L-aspartic acid activates the aforementioned receptors to transmit excitation.
Exposure to an excess amount of NMDA, AMPA or kainic acid causes neuronal cell death. It has been reported that 2-amino-5-phosphonovaleric acid and 2-amino-7-phosphonoheptanic acid, both of which are selective NMDA antagonists, are protective against NMDA excitotoxicity or in experimental animal models for epilepsy, cerebral ischemia, etc. (J. Pharmacology and Experimental Therapeutics, 250, 100 (1989): J. Pharmacology and Experimental Therapeutics, 240, 737 (1987): Science, 226, 850 (1984)).
It has been reported that the NMDA receptor is under allosteric control by glycine (Nature, 325, 529 (1987)).
Glycine exerts its effect via a glycine receptor located on the NMDA receptor. It has been reported that HA-966, which is a glycine antagonist, is effective in an experimental animal model for cerebral ischemia (Society for Neuroscience, Annual Meeting Abstract, 1989).
It has also been reported that NBQX (6-nitro-7-sulfamoylbenzo[f]quinoxaline), which is a selective AMPA antagonist, is effective in the experimental animal model for cerebral ischemia (Science, 247, 571 (1990)).
It has been reported that the AMPA receptor usually undergoes very rapid desensitization (Proc. Natl. Acad. Sci. USA, 85, 2834 (1988)). It is considered that this action protects neurons from excessive excitation by glutamic acid (Neuron, 5, 61 (1990)). As a desensitization inhibitor there has been found cyclothiazide (J. Neurosci., 13, 3904 (1993), which has been reported to accelerate AMPA-induced cell death (J. Neurochem., 60, 1171 (1993)). It has also been reported that GYKI52466, which had been known as a noncompetitive AMPA antagonist (Neurosci. Lett., 125, 5 (1993)), counteracts the inhibition of desensitization by cyclothiazide (Neuron, 10, 51 (1993)), and that this agent is effective in an experimental animal model for cerebral ischemia (Stroke, 23, 861 (1992)).
Some pyridothiazine derivatives have been reported (Collect. Czech. Chem. Commun., 48, (11), 3315 (1983); Rocz. Chem., 49 (4), 748 (1975); Acta. Polon. Pharm., 38 (2), 145 (1981); Il Farmaco. Ed. Sc., 41 (12), 964 (1986)). However, these pyridothiazine derivatives have been merely reported for the anti-serotonin, anti-spasm, antidepressant, and analgesic, and anti-inflammation effects. These pyridothiazine derivatives have never been known to act as noncompetitive antagonists at AMPA receptor and inhibit the kainic acid neurotoxicity.